Alternative poly(A) site selection in complex transcription units: means to an end?

Abstract

Many genes have been described and characterized which result in alternative polyadenylation site use at the 3'-end of their mRNAs based on the cellular environment. In this survey and summary article 95 genes are discussed in which alternative polyadenylation is a consequence of tandem arrays of poly(A) signals within a single 3'-untranslated region. An additional 31 genes are described in which polyadenylation at a promoter-proximal site competes with a splicing reaction to influence expression of multiple mRNAs. Some have a composite internal/terminal exon which can be differentially processed. Others contain alternative 3'-terminal exons, the first of which can be skipped in some cells. In some cases the mRNAs formed from these three classes of genes are differentially processed from the primary transcript during the cell cycle or in a tissue-specific or developmentally specific pattern. Immunoglobulin heavy chain genes have composite exons; regulated production of two different Ig mRNAs has been shown to involve B cell stage-specific changes in trans -acting factors involved in formation of the active polyadenylation complex. Changes in the activity of some of these same factors occur during viral infection and take-over of the cellular machinery, suggesting the potential applicability of at least some aspects of the Ig model. The differential expression of a number of genes that undergo alternative poly(A) site choice or polyadenylation/splicing competition could be regulated at the level of amounts and activities of either generic or tissue-specific polyadenylation factors and/or splicing factors.

Ending the message: poly(A) signals then and now

“…However, a significant part of mRNA size variation derives not from alternative splicing, but rather from alternative PAS selection. Thus, it is calculated that well over half of all mRNAs have variable PAS selection, meaning that they will possess mRNA isoforms differing by the extent of their 39 UTRs (Edwalds-Gilbert et al 1997;Tian et al 2005). Since mRNA 39-end processing occurs cotranscriptionally and is stimulated by Pol II CTD (Proudfoot 2004), it is clear that once a particular PAS has been selected and mRNA 39 cleavage occurs with consequent release from chromatin-associated Pol II, then further cleavage of more proximal PAS on the mRNA will not occur.…”

Synaptic Activity-Induced Conversion of Intronic to Exonic Sequence in Homer 1 Immediate Early Gene Expression

“…Detection of inducible intranuclear foci thus provides a powerful tool to assess exon and intron sequences that are transcribed rapidly in response to MECS. Absence of intranuclear signal with probes beyond intron 5 thus indicates that activityinduced Homer 1 transcripts stop prematurely (Uptain et al, 1997) within intron 5, possibly facilitated by alternative poly(A) site selection (Edwalds-Gilbert et al, 1997).…”

Inefficient processing of mRNA for the membraneform of IgE is a genetic mechanism to limit recruitment of IgE‐secreting cells

“…The expression of the two forms is regulated by alternative splicing and/or polyadenylation of the premRNA transcripts for the Ig HC genes [11]. The constant domains of the murine HC are encoded in three (IgD and IgG) or four exons (IgM and IgE), while the transmembrane domain and the cytoplasmic tail are encoded in two additional exons (M1 and M2), with the exception of IgA, in which both domains are encoded in one exon (Fig.…”

“…The choice depends normally on the developmental stage of the B cell [11][12][13][14][15]. In resting B cells the ratio is approximately 1 : 1 for the mu (l) HC, but this ratio shifts in favor of the secreted form in plasma cells, resulting in a ratio of approximately 1 : 100 for the membrane (ml) versus the secreted form (sl), respectively.…”